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Novel membrane-based targets – Therapeutic potential in gynecological cancers M. Gizzi a,b , P. Pautier a , C. Lhomme a , A. Leary a,∗ b

a Department of Medicine, Gustave Roussy, University of ParisSud, Villejuif, France Medical Oncology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium

Accepted 28 October 2014

Contents 1. 2.

3.

4.

5. 6. 7. 8.

9.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidermal growth factor receptor inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Early trials in unselected patients disappointing results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Next generation epidermal growth factor receptor inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Pertuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. MM121 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. The future of HER targeting in gynecological cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin growth factor-like receptor-1 (IGF1R): an old target new drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Relevance of the IGF1R axis to gynecological tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. IGF1R antibodies in gynecological cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Tyrosine kinase inhibitors (TKIs) of IGF1R and insulin receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting MET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. MET: relevance in gynecological cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Lessons from other tumor types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Multitargeted MET inhibitors in gynecological cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The fibroblast growth factor receptor family (FGFR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTCH receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug immunoconjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Folate receptor-␣ (FR␣) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Luteinizing hormone releasing hormone (LHRH) receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Anti –NaPi2b – monomethyl auristatin E (MMAE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Recent advances have been made in the molecular profiling of gynecological tumors. These discoveries have led to the development of targeted therapies that have the potential to disrupt molecular pathways involved in the oncogenesis or tumor progression. In this review, we highlight areas of recent progress in the field of membrane receptor inhibitors in gynecological malignancies and describe the biological rationale underlying the inhibition of these receptors. We will introduce drug immuno-conjugates, and give an update on the biological ∗

Corresponding author at: Department of Medicine, Gustave Roussy, University of ParisSud, Villejuif, France. Tel.: +33 0142115276; fax: +33 0142115230. E-mail addresses: [email protected] (M. Gizzi), [email protected] (A. Leary).

http://dx.doi.org/10.1016/j.critrevonc.2014.10.015 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Gizzi M, et al. Novel membrane-based targets – Therapeutic potential in gynecological cancers. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.015

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rationale and the clinical studies involving agents directed against EGFR, HER3, IGFR, MET, FGFR, NOTCH, and TRAIL. We also discuss the challenge facing these new therapies. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Targeted therapies; Membrane receptor inhibitors; Gynecological malignancies

1. Introduction Thanks to recent large-scale molecular profiling studies in ovarian [1], endometrial [2] and cervical [3] cancers, such as the integrated genomic analyses performed by the Cancer Genome Atlas (TCGA) network, significant headway has been made in the molecular profiling of gynecological malignancies. Unfortunately these advances have not yet translated into meaningful clinical benefit for patients. Over the last two decades, clinical trials with epidermal growth factor receptor (EGFR) inhibitors conducted in women with gynecological cancers have been resoundingly negative [4]. However, there may be cause for optimism. Therapeutic strategies aimed at novel membrane-based targets are being investigated and may offer real hope for the future of membrane receptor inhibitors in gynecological malignancies. This review will present an update of inhibitors of novel membrane-based targets at various stages of clinical development in gynecological cancers such as agents directed against HER3, HER2-containing heterodimers, as well as the receptors for MET, Folate, Fibroblast growth factor, Notch or Trail (tumor-necrosis-factor related apoptosis-inducing ligand). The therapeutic potential of drug immuno-conjugates targeted to membrane based tumor associated antigens in gynecological oncology will also be introduced. Finally, the biological rationale for specific membrane receptor inhibitors in molecularly selected gynecological tumors will be addressed, and some of the challenges facing these new therapies will be discussed.

2. Epidermal growth factor receptor inhibitors 2.1. Early trials in unselected patients disappointing results EGFR was identified several decades ago as an attractive target in gynecological tumors because of its frequent overexpression [5]. Unfortunately a number of clinical trials conducted in women with ovarian, endometrial or cervical cancers failed to demonstrate any clinical activity for either antibodies or small molecule inhibitors of EGFR [6–8],4 . Results of trials targeting the human epidermal growth factor receptor 2(HER2) receptor were also disappointing [9]. One explanation frequently proposed to account for the observed lack of activity is that these trials were conducted in an unselected population. Given the observation that a

significant proportion of type I endometrial cancers (EC) demonstrate significant HER2 overexpression or amplification [10], one study of trastuzumab was conducted in advanced endometrial cancer with HER 2+/3+ or HER2 amplification by FISH (fluorescent in situ hybridization). No objective responses were observed among the 18 patients with documented HER2 amplification [11]. HER2 amplification is relatively common (18.2%) in ovarian mucinous carcinomas although not necessarily of prognostic significance. Response to conventional therapy is limited in this histologic subtype of OC and trastuzumab may provide a treatment option for patients with mucinous carcinoma when the tumor has HER2 amplification and overexpression [12]. 2.2. Next generation epidermal growth factor receptor inhibitors In the last 10 years, an improved understanding of the structure, function and interaction between individual epidermal growth factor receptors has led to the identification of new therapeutic strategies [13]. EGFR, HER3 and HER4 require ligand for activation and undergo homo- or heterodimerization with another partner. HER2 has no ligand, and its activation occurs via homo-dimerization in the setting of significant HER2 overexpression, or because the receptor is recruited to heterodimerize with another family member (Fig. 1). 2.2.1. Pertuzumab Pertuzumab was developed as an antibody that could interfere with HER2-containing heterodimers. As such it may have activity in HER2 non-amplified cancers driven by HER2 containing heterodimers and/or high levels of circulating HER ligands. Although pertuzumab can no longer truly be qualified as a ‘novel’ therapy since it has now received Federal Drug Administration (FDA) approval in HER2+ breast cancer [14], the novelty is investigating its activity in nonHER2 amplified cancers. A first phase II trial suggested that the benefit of pertuzumab might be limited to patients with putatively activated HER2 signaling as measured by phosphorylated HER2 levels [15]. A follow-up study randomized patients with advanced platinum resistant ovarian cancer to gemcitabine alone or in combination with pertuzumab and the investigators sought to explore efficacy in the subset with activated HER2 signaling–as measured by gene expression levels of EGFR, HER2, HER3 and their ligands. Again no benefit

Please cite this article in press as: Gizzi M, et al. Novel membrane-based targets – Therapeutic potential in gynecological cancers. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.015

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A

HER2/HER3 Amp 7% HGSOC

EGFR M+ 5-10% HGSOC 4% of CC 3% of EC

EGF EGFR

B

HER3

EGF NRG1 AREG NRG2 EREG

EGFR

HER2

HER3

HER2

3

HER2 M+ 10% serous OC HER2 Amp+ 20% mucinous OC 15% clear cell OC 30% Type 2 EC

C

HER3 receiver

donor

Fig. 1. The future of HER targeted therapies in gynecological cancers: selecting patients? (A) By genomic alterations: Frequency of mutations (M+) or amplification (Amp+) of epidermal receptors in ovarian, endometrial and cervical cancers. (B) High levels of ligand for EGFR (EGF, amphiregulin and epiregulin), or for HER3 (neuregulins) may be relevant to HER activation and sensitivity to inhibitors. (C) Novel assays may detect protein–protein interactions such as HER heterodimers: these require the proximity of an antibody pair for light-dependent release of a fluorescently labeled tag. Abbreviations: EGFR: epidermal growth factor receptor; HGSOC: high grade serous ovarian cancer; CC: cervical cancer; EC: endometrial cancer; EGF: epidermal growth factor; OC: ovarian cancer; AREG: amphiregulin; EREG: epiregulin; NRG: neuregulin.

was found in the group as a whole (PFS = 2.9 vs. 2.6 mo), but when considering the subset of tumors with low HER3 mRNA, the addition of pertuzumab to chemotherapy significantly prolonged PFS (5.3 vs 1.4 mo, p = 0.002). This led to the hypothesis that low HER3 mRNA could be a predictive marker for pertuzumab benefit [16]. The biological mechanism proposed to support this hypothesis was that low HER3 mRNA could be a surrogate marker for activated HER2:HER3 heterodimers. The phosphatidylinositol 3-kinase (PI3K) pathway is the main downstream effector from HER2:HER3 heterodimers and there are both preclinical and clinical data suggesting that PI3K signaling may lead to transcriptional repression of HER3. In line with this hypothesis, PI3K inhibition has been shown to re-activate HER3 expression in cell models and clinical samples [17]. Although a recently published randomized trial could not confirm a benefit for pertuzumab even in the low HER3 subset, this trial was conducted in platinum sensitive ovarian cancer [18]. An ongoing phase III randomized trial (PENELOPE) is investigating the benefit of combining pertuzumab with chemotherapy in platinum resistant ovarian cancer with low HER3 mRNA expression (NCT01684878).

2.2.2. MM121 The fully human monoclonal antibody against HER3, MM121 showed an encouraging 25% objective response rate (ORR) in combination with paclitaxel in a phase I trial [19]. A resulting phase II study is randomizing patients with platinum resistant ovarian cancer to paclitaxel alone or in combination with MM121 (NCT01447706). Importantly, tumor biopsies have been prospectively obtained in this study and may identify candidate predictive markers of sensitivity or resistance. 2.3. The future of HER targeting in gynecological cancers The only objective response to gefitinib described in OC was observed in a patient with an activating EGFR mutation [20]. Recent data from the TCGA in ovarian, endometrial and cervical cancers have demonstrated that although individual genomic alterations in growth factor receptors are rare, they are clearly documented (Fig. 1A). Of particular interest are novel activating mutations in HER2 described in 10% of lowgrade serous ovarian cancer [21]. Given the demonstrated activity of EGFR or HER2 inhibitors in EGFR mutated NSCLC and HER2 amplified breast cancer, respectively;

Please cite this article in press as: Gizzi M, et al. Novel membrane-based targets – Therapeutic potential in gynecological cancers. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.015

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there may be a rationale for testing EGFR/HER2 inhibitors in gynecological tumors harboring EGFR or HER2 mutations. In addition to genomic alterations, it is possible that other markers may be useful to select patients for EGFR (or in fact any membrane receptor) inhibitors (Fig. 1B and C). For example ligand levels may be relevant. Elevated levels of amphiregulin (AREG) or epiregulin (EREG) mRNA expression may predict benefit from cetuximab in colorectal cancer regardless of EGFR expression [22]. In addition measuring tumor heterodimer expression may provide useful predictive information [23]. Experimental assays measuring protein–protein interactions based on proximity of an antibody pair for light-dependent release of a fluorescently labeled tag [24] (Fig. 1C) are becoming available. If validated, they could provide a useful tool to evaluate the interaction between membrane receptors and measure heterodimer levels.

cross-reactivity as well as the formation of hybrid IR-IGF1R complexes [29]. Targeting both receptors simultaneously could lead to a more potent anti-tumor effect albeit at a risk for greater cumulative metabolic toxicity. An oral dual inhibitor of IGF1R and IR, linsitinib (OSI906) showed encouraging activity in combination with paclitaxel in a phase I trial in advanced ovarian and endometrial cancers [30]. A resulting phase I/II in platinum-resistant OC is randomizing patients to paclitaxel alone or in combination with linsitinib using intermittent or continuous dosing (NCT00889382). This drug accumulates poorly in muscle, the main site for insulin-mediated glucose uptake, which could explain the relatively good tolerance profile to date.

4. Targeting MET 4.1. MET: relevance in gynecological cancers

3. Insulin growth factor-like receptor-1 (IGF1R): an old target new drugs The IGF1R axis has attracted significant attention as a potential target for over a decade. Unfortunately despite a sound biological premise, strong preclinical data, and signs of activity in phase I/II trials, large phase III trials mainly conducted in other tumor types were disappointing [25]. Regardless, a huge number of novel antibodies or small molecule inhibitors are in development and at various stages of clinical testing. 3.1. Relevance of the IGF1R axis to gynecological tumors IGF1R expression is increased in tumor compared to normal tissue and is associated with poor prognosis in gynecological cancers [26]. Given the implication of the metabolic syndrome and insulin resistance in type I endometrial cancers (EC), the IGF1R axis may be particularly relevant [27]. 3.2. IGF1R antibodies in gynecological cancers Two IGF1R antibodies are being tested in ovarian cancer (OC). A single arm phase II study of the IGF1R antibody, AMG479 in platinum sensitive recurrent ovarian cancer showed very modest activity [28] and a phase II trial of adjuvant chemotherapy +/− AMG479 is ongoing in optimally debulked OC (NCT00718523). The combination of another IGF1R antibody, MK0646 with an mTOR or Akt inhibitor is being tested in platinum resistant OC and the trial recently completed accrual (NCT01243762). 3.3. Tyrosine kinase inhibitors (TKIs) of IGF1R and insulin receptor The IGF1R and insulin receptors (IR) share significant structural homology and interact with each other via ligand

MET (hepatocyte growth factor receptor) is a transmembrane receptor which is activated by hepatocyte growth factor (HGF, aka scatter factor) binding. Upon ligand induced dimerization, MET activates both the RAS-RAF-MEK and the PI3K-AKT pathways. In addition, the MET signaling cascade is quite promiscuous and interacts with a number of other signaling pathways such as EGFR, RET (rearranged during transfection), TIE2 (angiopoetin receptor-2) and vascular endothelial growth factor receptor (VEGFR); as such MET has frequently been implicated in resistance to targeted therapies [31]. MET amplifications have been identified in 12% of ovarian cancer; especially in clear cell OC (MET amplified in 20–30%) [32]. MET knock-down by shRNA in MET-amplified clear cell OC lines results in apoptosis and senescence supporting its role as a putative oncogenic driver in ovarian clear cell carcinogenesis [33]. In addition recent data from the TCGA suggest that mutations in the ligand, HGF or the receptor may be identified in 10% of endometrial cancers and a smaller number of cervical cancers [34]. 4.2. Lessons from other tumor types Drugs are in clinical development targeting the MET pathway either as MET antibodies, MET specific tyrosine kinase inhibitors, or most frequently as multitargeted MET inhibitors. Neither the MET antibodies nor the selective MET inhibitors are being specifically investigated in gynecological malignancies, however many of the MET selective TKIs in phase I trials are selecting patients with demonstrated MET alterations. Selective MET inhibition may not result in significant tumor shrinkage suggesting that MET may be more of a ‘facilitator’ than a ‘driver’ [35]. This taken together with the implication of MET in resistance to targeted therapies may provide the rationale for combining MET inhibition with other targeted therapies or using multi-targeted MET inhibitors.

Please cite this article in press as: Gizzi M, et al. Novel membrane-based targets – Therapeutic potential in gynecological cancers. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.015

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4.3. Multitargeted MET inhibitors in gynecological cancers Crizotinib was initially developed as an anaplastic lymphoma kinase (ALK) inhibitor for ALK-EMLA translocated non-small cell lung cancer [36]. However it also efficiently inhibits other tyrosine kinases such as ROS1 and cMET at sub-nanomolar concentrations. A ‘basket’study (The AcSéProgramme) is recruiting patients with tumors harboring alterations in Crizotinib targets for treatment with Crizotinib in France. Of particular interest is the cohort dedicated to MET amplified ovarian cancer (NCT02034981). Tumor hypoxia associated with anti-VEGF therapies leads to an up-regulation in hypoxia-inducible factor-alpha (HIF 1a) which in turn may increase levels of the MET ligand, HGF, as well as possibly increase MET transcription via a HIF1a responsive element in the receptors promoter [37]. Combined inhibition of MET and VEGFR may result in synergy. Cabozantinib is a dual VEGFR2/MET inhibitor that showed encouraging activity in a randomized discontinuation trial with a response rate of 24% among 68 patients with recurrent OC [38]. A phase II trial is ongoing and randomizing patients with platinum-resistant ovarian cancer to cabozantinib versus paclitaxel (NCT01716715). Another phase II trial is investigating the activity of cabozantinib in recurrent EC (NCT01815151). Both studies are recruiting unselected patients but correlative biological studies will investigate the relationship between MET alterations and response.

5. The fibroblast growth factor receptor family (FGFR) Fibroblast growth factor receptors are a family of 4 receptors expressed on both endothelial and tumor cells. Selective FGFR inhibitors have been developed based on the demonstration that tumors frequently demonstrate genetic alterations in one of the receptors. For example 10–20% of breast cancers display amplification in FGFR-1 [39]. FGFR2 activating mutations have also been identified in 12% of type I EC [40]. Importantly, EC cell lines harboring the FGFR-2 mutation are sensitive to selective FGFR inhibitors, thus providing preclinical evidence that FGFR-2 mutations may be oncogenic in EC [41]. As a result at least three FGFR inhibitors are being investigated in phase I trials in FGFR-2 mutated EC. Unfortunately, one trial testing the FGFR tyrosine kinase inhibitor FP-1039 has already closed as the original assumption was at least 5% of patients screened would qualify but screening of the first 70 patients failed to identify a single FGFR2 mutation. FGFR2 mutations are only described in 12% of Type I EC – which tend to have a good prognosis with few relapses – and may therefore be a rare event in poor prognosis EC (typically high grade Type II EC) considered for phase I trials. The TCGA has recently demonstrated

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mutations or amplifications of FGFR-1 or FGFR-3 in 10% of EC, whether these alterations could select patients for selective FGFR inhibitors should be investigated. FGFR inhibition has also been tested in ovarian cancer. Brivanib, an oral selective dual inhibitor of FGF and VEGF signaling, has been studied in a randomized phase II discontinuation trial in OC patients progressing after previous treatment, including antiangiogenic agents. PFS was doubled for brivanib compared to placebo (4 months vs 2 months) with a HR of 0.54 (90% CI: 0.28–1.03; p = 0.11). Clinical activity was observed in patients pre-treated with VEGF inhibitors (mainly bevacizumab, with 17% PR and 30% SD). Whether this effect is strictly due to FGF inhibition is uncertain [42]. Dovitinib, an inhibitor of FGFR/VEGFR/PDGFR signaling pathways, demonstrates significant antitumor activity in endometrial cancer cells with FGFR2 mutations [43]. Dovitinib enhances ER␣ expression in FGFR2 mutant EC cells. Combination of dovitinib plus fulvestrant resulted in a significant higher inhibition of cell growth than dovitinib treatment alone. These findings suggest that combinatory therapies using dovitinib plus fulvestrant treatment may be effective in EC patients carrying FGFR2 mutations [44].

6. NOTCH receptor Notch receptors are a family of highly evolutionary conserved receptors. Their activation requires cell-to-cell contact and binding with trans-membrane ligands such as Jagged1 or Delta like ligands (DLL) which leads to a series of cleavages via metalloproteinase and ␥-secretase, in order to release the receptor from the membrane and allow its translocation to the nucleus where it acts as a transcriptional factor (Figs. 2, 3a and b). Notch 3 amplifications have been described in 10–20% of OC. In addition, amplifications have been described in Notch ligands (Jagged-1) or Notch transcriptional co-activators (mastermind-like proteins, MAML1-3) so that dysregulated Notch signaling was found in 22% of high-grade serous ovarian cancer (HGSOC) analyzed in the TCGA. Notch3 overexpression has been associated with poor PFS in both ovarian and cervical cancers and implicated in epithelial to mesenchymal transition, in stem cell-ness and in platinum resistance. Finally Notch3 may be involved in the metastatic progression as expression levels increase with relapse [45]. The main challenge in the field of Notch inhibition has been the development of selective inhibitors. Agents at most advanced stages of development are ␥-secretase inhibitors. Because this enzyme has a number of substrates, inhibitors may be relatively non-specific and potentially toxic. The major dose limiting toxicity in clinical trials was gastrointestinal (GI) due to inhibition of Notch1 in intestinal goblet cells. Regardless a number of trials are exploring the activity of these agents in OC on the basis of frequent aberrant Notch

Please cite this article in press as: Gizzi M, et al. Novel membrane-based targets – Therapeutic potential in gynecological cancers. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.015

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Fig. 2. Notch receptor activation (adapted from Ersvaer E, Hatfield KJ, Reikvam H, Bruserud O – Bone Marrow Res (2010)). Signaling is initiated by membrane bound ligand binding to Notch receptor, this recruits ADAM family proteases and γ-secretase for a two-step proteolytic cleavage releasing the Notch Intracellular Domain (NICD) into the cytoplasm. The NCID translocates to the nucleus where it complexes with nuclear co-activators such as MAML and initiates the transcription of NOTCH target genes, including NFkB, mTOR, cyclin D1, c-myc, and AKT. Abbreviations: MMP: matrix metalloproteinase; NICD: Notch IntraCellular Domain; MAML: mastermind-like protein; NCoA: nuclear co-activator; nuclear factor kappa B; mTOR: mammalian target of rapamycin; AKT: protein kinase B.

signaling in this tumor (Table 1). A phase I trial is also recruiting patients in EC. A number of challenges face Notch inhibitors. First, preclinical data suggest that these drugs may have minimal effect on tumor shrinkage, the effect being primarily on PFS. The hypothesis being that Notch inhibition may act primarily on the cancer stem cell population [46]. It is likely that demonstration of deregulated Notch signaling in tumors will be required to expect a clinical benefit. Finally most currently available agents are pan-Notch inhibitors, however antibodies directed against specific Notch receptors including Notch3 are in development.

7. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors Trail binding to the receptor activates the extrinsic apoptotic pathway via caspases 8 and 10. Trail receptor agonists

have emerged as an attractive therapeutic strategy because they may be relatively cancer cell specific; as opposed to the other tumor necrosis factor (TNF) family of apoptosis inducing ligands, Trail selectively activates apoptosis in cancer cells but not healthy tissue [47]. In addition, because conventional anti-cancer therapies cause cells death via the intrinsic apoptotic pathway, there may be a strong rationale for combining Trail agonists with chemotherapy [48]. A phase II trial is on-going testing the combination of carboplatin and paclitaxel with the Trail-R2 agonist Tigatizumab as adjuvant treatment in ovarian cancer patients after suboptimal debulking (defined per protocol as more than one centimeter residual disease and RECIST measurable disease) (NCT00945191). On the basis of synergistic apoptotic effects of Trail-R agonists and radiation or cisplatin in cervical cell lines [49], a phase I/II trial is also ongoing evaluating the TRAIL-R1 agonist, mapatumumab, with concomitant radiotherapy and cisplatin in stage IB2 cervical cancer (NCT01088347).

Table 1 Ongoing phase I trials of NOTCH inhibitors in gynecological cancers. Trial type and tumor Phase I endometrial cancer Phase II ovarian cancer Phase I with ovarian expansion cohort Phase I with ovarian expansion cohort

Treatment ␥-Secretase inhibitor GSI (RO4929097) + Temsirolimus Single agent GSI (RO4929097) in recurrent OC GSI (MK0646) Dalotuzumab + mTOR inhibitor (Ridaforolimus) or AKT inhibitor (MK2206) Single agent pan-Notch inhibitor (BMS-906024)

NCT trial number NCT01198184 NCT01175343 NCT01243762 NCT01292655

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Fig. 3. Drug–antibody conjugates as a means of selective cytotoxic delivery. A cytotoxic is conjugated via a cleavable linker to ligand or antibody directed at a cell surface target. Upon binding to the cell surface protein, the complex is internalized and the cytotoxic is released for direct DNA damage and the receptor is recycled to the cell membrane.

8. Drug immunoconjugates Drug immunoconjugates are being developed as a strategy for tumor-specific chemotherapy delivery in order to maximize tumor cytotoxicity while sparing normal tissue. Antibodies or ligands for tumor-specific membrane proteins are linked via cleavable bonds to conventional cytotoxics. These compounds act like a “Trojan horse.” After binding to the membrane receptor, the complex is internalized, and the drug is released intracellularly by proteolytic cleavage for the purpose of selective tumor cell killing [50]. This strategy requires the demonstration that the membrane target of interest is preferentially expressed on the surface of tumor cells rather than normal tissue. At least nine immuno-conjugates are under development in gynecological malignancies (Table 2). 8.1. Folate receptor-α (FRα) The FR␣ has a high affinity for folate, which is transported into cells via receptor–ligand endocytosis. The receptor is overexpressed in 90% of non-mucinous OC [51] and type II endometrial cancers [52]. In contrast, normal tissues do not express significant FR␣ as folate is mainly transported via the reduced folate carrier. Selective tumor expression of FR␣ has provided the rationale for therapeutic targeting of FR␣ in gynecological cancers. Farletuzumab, a humanized antibody against FR␣, showed encouraging results in a phase II ovarian cancer trial [53], unfortunately a follow up randomized phase III of carboplatin and paclitaxel alone or in combination with farletuzumab failed to meet its primary PFS endpoint (NCT00849667).

EC145 (Vintafolide) is composed of folic acid conjugated to vinblastine via a cleavable linker and represents one of the first immunoconjugates developed for the treatment of gynecological tumors. Results from a phase II trial in platinum resistant OC showed a significant improvement in PFS with the addition of EC145 to pegylated liposomal Doxorubicin (PLD) (PFS = 22 vs. 12 wks p = 0.03) [54]. The investigators identified a predictive biomarker in the form of radiolabeled folic acid (EC20). Patients who expressed 100% positivity for the receptor using an EC20 labeled nuclear scan were found to derive greater benefit from the addition of EC145 (PFS = 24 wks vs. 6 wks p = 0.018). Unfortunately the ensuing phase III PROCEED trial (NCT01170650) of PLD alone or in combination with EC145 in platinum-resistant EC20-positive ovarian cancer closed in May 2014 after the interim analysis showed that the combination did not meet the efficacy hurdle pre-specified in the statistical analysis plan. 8.2. Luteinizing hormone releasing hormone (LHRH) receptors LHRH receptors are expressed in 80% of endometrial and ovarian cancers and have emerged as another target for tumor specific cytotoxic delivery. AEZS-108 is an LHRH agonist conjugated to doxorubicin via a protease cleavable linker. A phase II trial in LHRH receptor positive gynecological cancers showed activity in EC (RR = 31%, N = 43) and platinum-resistant OC (RR = 12%, N = 42) [55]. A phase III trial in relapsed EC previously treated with a platinum and taxane is comparing Doxorubicin to AESZ108; the trial is not selecting on the basis of LHRH receptor expression (NCT01767155). A similar compound, EP-100

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Table 2 Drug-immunoconjugates in early development in gynecological malignancies. 1. EC145: Folic acid-Vinblastine • 80% non-mucinous OC express FR␣ • Phase II trial showed improved PFS for EC145 + PLD vs. PLD alone in platinum-resistant OC (PFS = 22 vs. 12 wks p = 0.03)a • Phase III trial (EC145 + PLD vs PLD) stopped at interim. Failed to meet efficacy endpoint (NCT01170650) 2. MGN853: Anti-FR␣ Ab-DM4 • Phase I in OC and other FR␣+ cancers ongoing (NCT01609556) 3. BMS-753 493: Folic acid conjugated to epothilone A • Phase I/II study terminated (NCT00550017) 4. AEZS-108: LHRH agonist-doxorubicin • 80% OC and EC express LHRH receptors • Phase II trial showed activity of AEZS alone in previously treated LHRH receptor+ EC (RR = 31%) and platinum resistant OC (RR = 12%)b • A phase III trial is ongoing in platinum and taxane pretreated EC (NCT01767155) 5. EP-100: LHRH agonist-CLIP71 • Trial planned in LHRH receptor + platinum resistant OC (NCT01485848). 6. BB10901: Anti-CD56 Ab-DM1 • 48% serous OC express CD56 (NCAM, neural cell adhesion molecule)c • Phase I ongoing with OC expansion cohort (NCT00346385) 7. BAY949343: Anti-Mesothelin Ab-DM4 • Overexpressed in OC, mesothelioma and pancreatic cancer • Interim phase I reported shown to be safed 8. DMUC5754A: Anti-MUC16-MMAE • MUC16 expressed 80% OC • MUC16 involved in OC cell binding to the peritoneal cavity • MUC16 may suppress T-cell mediated host anti-tumor immunity • Phase I results: RR = 11% in platinum resistant OCe 9. DNIB0600A: Anti-NaPi2b-MMAE • NaPi2b = Sodium dependent phosphate transporter expressed in ovarian, lung and thyroid cancers. • Implication in cancer biology unknown. • Phase I results: RR = 41% at RP2D in NaPi2b positive OC (IHC 2+/3+) OCf • Phase II trial in platinum resistant OC ongoing (NCT01991210) Abbreviations: OC: ovarian cancer; FR␣: folate receptor; PFS: progression-free survival; PLD: pegylated liposomal doxorubicin; wks: weeks; LHRH: luteinizing hormone releasing hormone; EC: endometrial cancer; RR: response rate; CLIP71: membrane disrupting peptide; Ab: antibody; DM1: microtubule disrupting cytotoxic, emtansine; DM4: maytansine cytotoxic; MUC16: cell surface associated mucin 16; MMAE: monomethyl auristatin E; RR: response rate. *** Check DM1: auristatin.RW, Coleman RL, Burger RA, Sausville EA, Kutarska E, Ghamande SA, Gabrail NY, Depasquale SE, Nowara E, Gilbert L, Gersh RH, Teneriello MG, Harb WA, Konstantinopoulos PA, Penson RT, Symanowski JT, Lovejoy CD, Leamon CP, Morgenstern DE, Messmann RA. PRECEDENT: A Randomized Phase II Trial Comparing Vintafolide (EC145) and Pegylated Liposomal Doxorubicin (PLD) in Combination Versus PLD Alone in Patients With Platinum-Resistant Ovarian Cancer. J Clin Oncol. 2013 Dec 10; 31(35):4400–6.Emons, S. Tomov, P. Harter, J. Sehouli, P. Wimberger, A. Staehle, L. C. Hanker, F. Hilpert, P. Dall, C. Gruendker, AGO Study Group; Phase II study of AEZS-108 (AN-152), a target cytotoxic LHRH analog in patients with LHRH receptor positive platinum resistant ovarian cancer. 2010 ASCO annual meeting, Abstract number 5035.EV, Kairbayeva MZ, Nikogosyan SO, Mozhenkova AV, Digaeva MA, Tereshkina IV, Tupitsyn NN. Immunological peculiarities of CD-56-positive serous ovarian adenocarcinoma. Bull Exp Biol Med. 2010 Oct; 149(5):604–8.JC, Gordon MS, Hurwitz HI, Jones SF, Mendelson DS, Blobe GC, Agarwal N, Condon CH, Wilson D, Pearsall AE, Yang Y, McClure T, Attie KM, Sherman ML, Sharma S. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of Dalantercept, an activin Receptor-like Kinase-1 ligand trap, in patients with advanved cancer. Clin Cancer Res. 2014 Jan 15;20(2):480–9.J, Moore K, Birrer M, et al. Targeting MUC 16 with antibody-drug conjugate DMUC5754A in patients with platinum resistant ovarian cancer: A phase 1 study of safety and pharmacokinetics. AACR Annual Meeting. Abstract LB-290. Presented April 9, 2013.M, Gerber D, Infante J, Xu J, Shames D, Choi Y, Kahn R, Lin K, Wood K, Maslyar D, Burris H. A phase 1 study of the sagefty and pharmacokinetics of DNIB0600A, an anti-NaPi2b antibody–drug-conjugate, in patients with non-small cell lung cancer and platinum-resistant ovarian cancer. 2013 ASCO Annual meeting. Abstract 2507.

is an LHRH agonist linked to a membrane destabilizing peptide (CLIP71). A trial of EP-100 is planned in LHRH receptor-positive platinum resistant ovarian cancer (NCT01485848). 8.3. Anti –NaPi2b – monomethyl auristatin E (MMAE) The human sodium-dependent phosphate transporter NaPi2b is a protein receptor involved in the transcellular absorption of inorganic phosphate. Over-expression of this transporter was shown in non-mucinous ovarian cancer by

real time PCR and SAGE analysis. Its implication in oncogenesis is unknown and it seems that differential expression of NaPi2b may be the consequence of changes in ovarian epithelium differentiation during the malignant process [56]. DNIB0600A is a humanized IgG1 anti NaPi2b monoclonal antibody conjugated to the cytotoxic agent MMAE which resulted in a 41% response rate at the recommended phase II dose of 2.4 mg/kg every 3 weeks in NaPi2b positive (IHC 2+/3+) ovarian cancer [57] [58]. A phase 2 trial in platinum resistant OC comparing NaPi2b to PLD is ongoing (NCT01991210).

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9. Conclusion Thanks to recent advances in the molecular and genomic characterization of gynecological tumors, there may be real cause for optimism. A huge number of agents are investigating the benefit of targeting membrane receptors or cell surface proteins selectively overexpressed in gynecological malignancies. While most novel membrane receptor inhibitors are in early clinical trials, a number have reached the phase III trial stage (pertuzumab, vintafolide, AESZ-108). Many of these studies are being conducted in molecularly selected patients. The future of membrane receptor targeting in gynecological cancer will likely depend on careful patient selection. Given the low prevalence of many genomic alterations, some of these studies may be faced with prohibitively low accrual rates. The ‘basket’ study model has been proposed as way to address rare alterations across multiple tumor types. With the possible exception of cytotoxic immuneconjugates, selecting patients for specific inhibitors will require demonstration that the target is not only preferentially expressed on tumor cells but that the receptor is oncogenic, thus emphasizing the need for robust mechanistic studies in preclinical models with endogenous receptor expression. The question is whether any of these agents are likely to produce efficacy results comparable to anti-angiogenics or PARP inhibitors in gynecological malignancies. The antibody against VEGF, bevacizumab demonstrated RR of 15–20% in early phase II trials as a single agent in advanced OC – quite similar to the activity reported for the multitargeted inhibitors against MET, cabozantinib or FGFR, brivanib in advanced OC. It is likely that part of the benefit observed with these novel agents is attributable to their anti-angiogenic effects, however combining VEGF inhibition with MET or FGFR targeting may hold real promise, especially in biomarker selected patients (MET amplification). In 2015, it is likely that the first targeted therapy with an associated predictive biomarker will become available in gynecology – the PARP inhibitor, olaparib in BRCA mutated ovarian cancer. The priority must be matching novel membrane receptor inhibitors to biologically selected tumors. In this regard, FGFR inhibitors have focused on FGFR2 mutated EC, this may be a flawed strategy, since this alteration tends to be found in good prognosis well differentiated endometrioid tumors, often cured with local treatment alone. FGFR inhibitors may have a greater potential in higher grade poor prognosis EC which demonstrate FGFR1-3 amplifications. With regards to other membrane targets, the epidermal growth factor receptor inhibitors should be tested in EGFR or HER2 mutated or amplified gynecological malignancies. The future of IGF1R directed therapies may be limited unless robust predictive biomarkers can be identified. Candidate biomarkers for Notch inhibitors include amplifications in the receptor itself (Notch3), its ligands (Jagged), or in its transcriptional co-activators (MAML). Trail agonists may require combination with conventional chemotherapy or radiotherapy to optimize anti-tumor effect. Finally, ongoing studies will tell

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us whether drug immuno-conjugates have a real potential in gynecological malignancies. Conflict of interest The authors declare that they have no conflict of interest. Reviewers Jermaine Ian George Coward, MRCP, PhD, Senior Research Fellow, Mater Research, Translational Research Institute, Inflammation & Cancer Therapeutics Group, 37 Kent Street, Woolloongabba, Brisbane, QLD 4101, Australia. Rebecca Kristeleit, UCL Cancer Institute, School of Life and Medical Sciences, Gower Street, London WC1E 6BT, United Kingdom. References [1] Ying H, Lv J, Ying T, Jin S, Shao J, Wang L, et al. Gene–gene interaction network analysis of ovarian cancer using TCGA data. J Ovar Res 2013;6(88). [2] Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;(May). [3] http://www.cbioportal.org/public-portal [4] Haldar K, Gaitskell K, Bryant A, Nicum S, Kehoe S, Morrison J. Epidermal growth factor receptor blockers for the treatment of ovarian cancer. Cochrane Database Syst Rev 2011;10(October):CD007927. [5] Maihle NJ, Baron AT, Barrette BA, Boardman CH, Christensen TA, Cora EM, et al. EGF/ErbB receptor family in ovarian cancer. Cancer Treat Res 2002;107:247–58. [6] Konner J, Schilder RJ, DeRosa FA, Gerst SR, Tew WP, Sabbatini PJ, et al. A phase II study of cetuximab/paclitaxel/carboplatin for the initial treatment of advanced-stage ovarian, primary peritoneal, or fallopian tube cancer. Gynecol Oncol 2008;110(2):140–5. [7] Schilder RJ, Sill MW, Lee YC, Mannel R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Int J Gynecol Cancer 2009;19(5):929–33. [8] Gui T, Shen K. The epidermal growth factor receptor as a therapeutic target in epithelial ovarian cancer. Cancer Epidemiol 2012;36(October (5)):490–6. [9] Vaidya AP, Parnes AD, Seiden MV. Rationale and clinical experience with epidermal growth factor receptor inhibitors in gynecologic malignancies. Current Treatment options Oncol 2005;6(March (2)):103–14. [10] Rolitsky CD, Theil KS, McGaughy VR, Copeland LJ, Niemann TH. HER-2/neu amplification and overexpression in endometrial carcinoma. Int J Gynecol Pathol 1999;18(April (2)):138–43. [11] Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, et al. Phase 2 trial of trastuzumab in women with advanced or recurrent, Her2 positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2010;116(January (1)):15–20. [12] McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Köbel M, et al. HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer 2009;9(December):433. [13] Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5(May (5)):341–54. [14] Baselga J, Cortès J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366(January (2)):109–19.

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in patients (pts) with non-small cell lung cancer (NSCLC) or platinumresistant ovarian cancer (OC). 2014 Asco Annual meeting; abstract 2504.

Biography Alexandra Leary, MD, PhD is a medical oncologist and translational researcher specializing in gynecological tumors at Gustave Roussy. After obtaining a medical degree from Georgetown University Medical School and completing an Internal Medicine Residency at Northwestern University Hospital in Chicago, she pursued her training in Medical Oncology at the Royal Marsden Hospital in London and obtained a PhD from the Institute of Cancer Research/University of London. Since 2011, she has worked at Gustave Roussy as a medical oncologist treating ovarian, endometrial and cervical cancers with a special focus on early phase drug development and is the lab leader for gynecological tumors’ translational research within INSERM U981, Predictive Biomarkers and Novel Targeted Therapeutics Laboratory at Gustave Roussy.

Please cite this article in press as: Gizzi M, et al. Novel membrane-based targets – Therapeutic potential in gynecological cancers. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.015

Novel membrane-based targets - Therapeutic potential in gynecological cancers.

Recent advances have been made in the molecular profiling of gynecological tumors. These discoveries have led to the development of targeted therapies...
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